ORGANIC LETTERS
Asymmetric Synthesis of 2-Alkenyl-1-cyclopentanols via Tin−Lithium Exchange and Intramolecular Cycloalkylation
2002 Vol. 4, No. 13 2189-2192
Guido Christoph and Dieter Hoppe*,† Organisch-Chemisches Institut, Westfa¨ lische Wilhelms-UniVersita¨ t Mu¨ nster, Corrensstrasse 40, D-48149 Mu¨ nster, Germany
[email protected] Received April 23, 2002
ABSTRACT
We report a method for the synthesis of chiral cyclopentanes using tin−lithium exchange and cycloalkylation reactions. The sec-butyllithium/ (−)-sparteine-mediated deprotonation of an alkyl carbamate and subsequent substitution furnishes a highly enantioenriched stannane as a stable carbanion equivalent. It was transformed into suitable cyclization precursors, which underwent tin−lithium exchange and stereoselective cycloalkylation when reacted with n-butyllithium, giving highly enantioenriched cyclopentanes in very good yields. A kinetic resolution was observed with a higher substituted stannane.
The asymmetric deprotonation1 of achiral 5-alkenyl carbamates of type 1 by sec-butyllithium/(-)-sparteine 5 followed by a 5-exo-trig cyclization2 was found to be a powerful route to 2-substituted cyclopentanols 4 (Scheme 1).3 The cyclocarbolithiation4 proceeds with strict stereoretention at C-1 and a high diastereofacial selection at the double
Scheme 1.
Cyclocarbolithiation of 1a
†
Fax: (+49) 251-8336531. (1) (a) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem. 1990, 102, 1457-1459; Angew. Chem., Int. Ed. Engl. 1990, 29, 1422-1423. For reviews, see: (b) Hoppe, D.; Hense, T. Angew. Chem. 1997, 109, 23762410; Angew. Chem., Int. Ed. Engl. 1997, 36, 2282-2316. (c) Beak, P.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552-560. (d) Basu, A.; Thayumanavan, S. Angew. Chem. 2002, 114, 740763; Angew. Chem., Int. Ed. 2002, 41, 716-738. (2) (a) Bailey, W. F.; Ovaska, T. V. In AdVances in Detailed Reaction Mechanisms; Coxon, J. M., Ed.; JAI Press: Greenwich, CT, 1994; Vol. 3, pp 251-273. (b) Bailey, W. F.; Gavaskar, K. V. Tetrahedron 1994, 50, 5957-5970. (3) Woltering, M. J.; Fro¨hlich, R.; Hoppe, D. Angew. Chem. 1997, 109, 1804-1805; Angew. Chem., Int. Ed. Engl. 1997, 36, 1764-1766. (4) (a) Klein, S.; Marek, I.; Poisson, J.-F.; Normant, J. F. J. Am. Chem. Soc. 1995, 117, 8853-8854. (b) Review: Marek, I. J. Chem. Soc., Perkin Trans. 1 1999, 535-544. (c) Marek, I.; Normant, J. F. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; pp 271-337. 10.1021/ol026068w CCC: $22.00 Published on Web 05/25/2002
© 2002 American Chemical Society
a (a) (i) 1.5 equiv of sBuLi/(-)-sparteine 5, Et O, -78 °C, 202 30 h; (ii) El-X, -78 °C to rt.
bond, which leads to a mesomerically stabilized benzyl anion. Noteworthy, the strong directing power of the carbamate group overrides the inherent acidity of the C-4 protons in 1.
The concept could be extended to a number of substituted alkenyl-, alkynyl-, and alkadienyl carbamates.5 The reaction requires a carbanion-stabilizing substituent in the 6-position. Intramolecular allylic substitution extends the scope, but it is only applicable to allylic carbamates.6 Allylic chlorine in compound 1 (R ) CH2Cl) does not survive the conditions of R-deprotonation. As a result, we introduced a tributylstannyl group at an early stage as a chiral carbanion equivalent,7 which could be carried through the synthesis and converted stereospecifically to lithium in the presence of sensitive functionality. The use of enantioenriched R-oxy-stannanes and R-stannylated N-heterocycles for stereoselective cyclizations has been described in the literature.8 Deprotonation of the 5-TBSO-pentyl carbamate 6 by secbutyllithium/(-)-sparteine and subsequent quench with tributyltin chloride afforded the enantiopure stannane (S)-7 with 85% yield (Scheme 2). The (S)-configuration of 7 is a
which was stated in numerous examples.1b Compound 7 was converted into the allyl chloride 11 by standard steps. The treatment of 11 in ethereal solution with 1.5 equiv of n-butyllithium at -78 °C led to a rapid tin-lithium exchange under retention of configuration, followed by a highly stereoselective cyclization. The formed trans-configured product 15 was isolated in essentially quantitative yield as a single diastereomer and enantiomer (Scheme 3).9,10
Scheme 3.
Cyclization to the 2-Vinylcyclopentanol 15
a (a) 1.5 equiv of nBuLi, Et O, -78 °C, 96% (X ) Cl), 82% 2 (X ) OMe), 44% (X ) OTMS), [R]20D ) -50.2 (c 0.99, CH2Cl2).
Scheme 2.
Synthesis of Cyclization Precursors 11-13a
Similar results, albeit in lower yields, were obtained when the methyl ether 12 or the silyl ether 13 were employed (Scheme 3). These reactions can be rationalized as intramolecular SN2′ substitutions of the allylic leaving groups by a lithium carbanion nucleophile. The structure elucidation and the determination of the enantiomeric excess were accomplished, as outlined in Scheme 4, by the conversion of 15 to the vinylcyclopentanol
(a) (i) 1.4 equivof sBuLi, 1.5 equiv of (-)-sparteine 5, -78 °C, Et2O; (ii) 1.7 equiv of Bu3SnCl, -78 °C to rt, 85%; (b) TBAF, Et2O, rt, quant; (c) Swern oxidation, 93%; (d) (EtO)2P(O)CH2CO2Et, DBU, LiCl, CH3CN, rt, 94%, E/Z > 97:3; (e) DIBAL, THF, -78 °C, 98%; (f) KHMDS, MsCl, LiCl, THF, -78 °C to rt, 93%; (g) LiHMDS, MeOTf, THF, -78 °C to rt, 78%; (h) LiHMDS, TMSCl, -78 °C to rt, THF, 75%. a
Scheme 4.
Structure Elucidation of Cyclization Product 15a
consequence of the high pro-S-selectivity in the deprotonation and the retention in the substitution step of alkyl carbamates, (5) (a) Hoppe, D.; Woltering, M. J.; Oestreich, M.; Fro¨hlich, R. HelV. Chim. Acta 1999, 82, 1860-1877. (b) Oestreich, M.; Fro¨hlich, R.; Hoppe, D. J. Org. Chem. 1999, 64, 8616-8626. (c) Oestreich, M.; Hoppe, D. Tetrahedron Lett. 1999, 40, 1881-1884. (d) Tomooka, K.; Komine, N.; Sasaki, T.; Shimizu, H.; Nakai, T. Tetrahedron Lett. 1998, 39, 9715-9718. (e) For an inter-/intramolecular carbolithiation, see: Wei, X.; Taylor, R. J. K. Angew. Chem. 2000, 112, 419-422; Angew. Chem., Int. Ed. 2000, 39, 409-412. (6) (a) Deiters, A.; Hoppe, D. J. Org. Chem. 2001, 66, 2842-2849. (b) Deiters, A.; Mu¨ck-Lichtenfeld, C.; Fro¨hlich, R.; Hoppe, D. Chem. Eur. J. 2002, 8, 1833-1842 and references therein. (7) Still, W. C.; Sreekumar, C. J. Am. Chem. Soc. 1980, 102, 12011202. (8) (a) Tomooka, K.; Komine, N.; Nakai, T. Tetrahedron Lett. 1997, 38, 8939-8942. (b) Coldham, I.; Lang-Anderson, M. M. S.; Rathmell, R. E.; Snowden, D. J. Tetrahedron Lett. 1997, 38, 7621-7624. (c) Coldham, I.; Ferna`ndez, J.-C.; Price, K. N.; Snowden, D. J. J. Org. Chem. 2000, 65, 3788-3795. (d) Ashweek, N. J.; Coldham, I.; Snowden, D. J.; Vennall, G. P. Chem. Eur. J. 2002, 8, 195-207. (e) Serino, C.; Stehle, N.; Park, Y. S.; Florio, S.; Beak, P. J. Org. Chem. 1999, 64, 1160-1165. For the synthesis of enantioenriched R-oxy-stannanes, see: (f) Tomooka, K.; Igarashi, T.; Nakai, T. Tetrahedron Lett. 1994, 35, 1913-1916. 2190
a (a) (i) MeSO H, MeOH, reflux; (ii) K CO , reflux, 81%; (b) 3 2 3 Swern, 93%; (c) PhCH2PPh3Br, KOtBu, Et2O, -40 °C to rt, 93%, E/Z ) 72:28; (d) 1.5 equiv of nBuLi, Et2O, -78 °C, 56%, [R]20D ) -21.9 (c 1.11, CH2Cl2) (lit.3 [R]20D ) -20.9 (c 0.98, CH2Cl2)).
16. Comparison of the 1H NMR spectra of 16 and of the known racemate11 confirmed the trans configuration. The (9) Representative Cyclization Procedure. A solution of the allyl chloride 11 (169 mg, 0.285 mmol) in dry Et2O (3 mL) under an atmosphere of argon in a flame-dried flask, sealed with a rubber septum, was cooled to -78 °C. n-Butyllithium (0.27 mL, 0.43 mmol, 1.5 equiv; 1.6 M in hexanes) was added dropwise, and the mixture was stirred for 2 h. After quenching with MeOH (0.2 mL) and H2O (0.1 mL) at -78 °C, the mixture was allowed to warm to rt, dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography (silica gel, petroleum ether to Et2O/petroleum ether ) 1:4) afforded the product 15 as a colorless oil (73 mg, 0.273 mmol, 96%; [R]20D ) -50.2 (c 0.99, CH2Cl2)). (10) All new compounds were characterized by 1H NMR, 13C NMR, IR, MS, and elemental analysis. Org. Lett., Vol. 4, No. 13, 2002
ee was determined to be >95% by chiral GC. The application of the tin-lithium exchange/asymmetric cyclization protocol to the 6-phenyl-5-hexenyl stannane 17 afforded the known cyclopentane 4 (El ) H), which is identical in all respects with a sample from the direct deprotonation/cyclocarbolithiation. Therefore, the retention of configuration at C-1 in the course of the tin-lithium exchange is confirmed. These encouraging results led us to the question what influence the exchange of a hydrogen by a methyl group at the carbon bearing the leaving group would have concerning the configuration of the product, either to the cis/transgeometry in the ring and/or to the E/Z-geometry of the newly built double bond. The methyl ether 19 was prepared in a similar fashion as compound 12. Application of the standard cyclization conditions (-78 °C, 2 h) to 19 gave exclusively the (E)configured cyclization product 20 as a single diastereomer (1,2-trans) but in a poor yield (Scheme 5). In addition, the
Scheme 5.
Synthesis and Cyclization of Methyl Ether 19a
Table 1. Cyclization of Pure C-7 Epimers (7R)- and (7S)-19
entry
config 19a
yield 19b
yield 20
yield 21
RD 21
1 2 3
7RS 7R 7S
69%c 96% 86%
37%d 74%d,e 6%d
57% 25% 13%f
-13.5 +21.4 -25.3
a Configuration at C-7. b Over two steps (reduction/methylation). c The reduction was carried out with DIBAL; see Scheme 5. d E/Z > 97:3. e [R]20D ) -61.4 (c 1.515, CH2Cl2). f Most of the starting material decomposed under the reaction conditions.
Analogously, we examined the influence of the double bond geometry in the cyclization precursor 19. However, the reaction of both C-7 epimers of 23 that are derived from the alcohol 8 via the phosphonium salt 22 afforded at -78 °C only the destannylated compound 24; no cyclization product was detected (Table 2). Ring closure to 20 occurred
Table 2. Cyclization of (Z)-Methyl Ethers (7R)- and (7S)-23 a
(a) Swern oxidation, 93%; (b) (EtO)2P(O)CH2C(O)CH3, DBU, LiCl, CH3CN, rt, 58%, E/Z > 97:3; (c) DIBAL, THF, -78 °C, 88%; (d) KHMDS, MeOTf, Et2O, -78 °C to rt, 78%; (e) 1.5 equiv of nBuLi, Et2O, -78 °C. 20: [R]20D ) -62.6 (c 0.38, CH2Cl2).
destannylated compound 21 showed a considerable optical activity, which led us to the assumption of a kinetic resolution in the cyclization step.12 Thus, with the intention of proving this hypothesis, the methyl ethers (7R)- and (7S)-19 were prepared by an enantioselective CBS-reduction13 as the key step and submitted to the standard cyclization conditions, i.e., 1.5 equiv of n-butyllithium at -78 °C for 2 h (Table 1). These experiments furnished the cyclization product 20 in 74% yield from (R)-19. In comparison with that, the reaction of (S)-19 afforded only traces of 20. The different ability of the pure diastereomers 19 to undergo the cyclization (Scheme 6, entries 2 and 3) gives strong support for an efficient kinetic diastereomer resolution. (11) Hoffmann, R. W.; Niel, G. Liebigs Ann. Chem. 1991, 1195-1201. (12) (a) For a kinetic resolution in the cyclization step of an enantioselective carbolithiation, see ref 5d. (b) A cyclization onto a trisubstituted methyl allyl ether without kinetic resolution is described by Broka et al. There, primary stannanes were used, and the reaction mixture was allowed to warm from -78 to 0 °C: Broka, C. A.; Lee, W. J.; Shen, T. J. Org. Chem. 1988, 53, 1338-1340. (13) Review: Corey, E. J.; Helal, C. Angew. Chem. 1998, 110, 20922118; Angew. Chem., Int. Ed. 1998, 37, 1986-2012. Usually, the (R)-CBSoxazaborolidine furnishes the (S)-alcohol, and the (S)-CBS-oxazaborolidine gives the (R)-alcohol. According to the published closely related examples, the de is assumed to be >95%. Org. Lett., Vol. 4, No. 13, 2002
entry 1 2 3 4
config 23a
yield 23
T (°C)
yield 20
yield 24
RD 24
7S 7S 7R 7R
77%b
-78 -40 -78 -40
0% 35%c 0% 37%d
96% 14% 32% 26%
-6.3 e +0.8f e
66%b
a Configuration at C-7. b E/Z < 3:97. c E/Z > 97:3, [R]20 ) -58.6 D (c 0.145, CH2Cl2). d E/Z > 97:3, dr ) 95:5, [R]20D ) -51.1 (c 0.73, e f CH2Cl2). Not determined. Partial racemization occurred in the course of the synthesis of (R)-2-methoxypropanal.15
when the temperature was raised to -40 °C.14 Again, 20 was isolated as a single stereoisomer (1,2-trans, 2(1E)), but with rather poor yield. In summary the configuration at C-7, as well as the double bond geometry, in the cyclization precursors 19 and 23 have no effect on the stereochemistry of the product 20. Both influence only the cyclization rate of the compounds 19 and 23. (14) Higher temperatures have not been applied, as the configurational and thermal stability of the intermediate R-oxy lithium compound is certain only below -40 °C.7 2191
cyclopentanols. The chiral precursors are easily prepared by the sec-butyllithium/(-)-sparteine deprotonation method and subsequent stannylation; the stannane unit, as a chiral carbanion equivalent, was maintained during the construction of the alkyllithium-sensitive internal allylic moiety. Another application is reported in the following paper.16 Expanding the scope of this asymmetric cyclization method to further carbo- and heterocycles is in progress and will be published in due course.
Table 3. Synthesis and Cyclization of Acetal 25
entry
E/Z 25
T (°C)
1 2
< 3:97 < 3:97
-78 -40
a
yield 26
E/Z 26
yield 27
14%b 82%c
>97:3 95:5
81% 11%
Acknowledgment. This work was supported by the Deutsche Forschungsgemeinschaft (Sonderforschungs-bereich 424). We thank Mrs. C. Weitkamp for her skillful experimental assistance.
Isomers are separatable. b [R]20D ) -66.2 (c 1.07, CH2Cl2). c dr ) 95:5.
Similar results as for 23 were obtained in the cyclization of the acetal 25 (Table 3). No cyclization was observed when employing the standard cyclization conditions (2 h, -78 °C), as outlined in Table 3. Cyclization occurred when the reaction was accomplished at -40 °C, affording the (E)configured enol ether 26 in good yield. In summary, we have shown that tin-lithium exchange followed by intramolecular cycloalkylation proceeds with very high stereoselection to furnish new enantioenriched
2192
Supporting Information Available: Detailed experimental procedures for the cyclizations and spectroscopic data for the compounds 4, 7, 15, 16, 20, 21, 24, 26, and 27. This material is available free of charge via the Internet at http://pubs.acs.org. OL026068W (15) Asao, N.; Shimada, T.; Sudo, T.; Tsukada, N.; Yazawa, K.; Gyoung, Y. S.; Uyehara, T.; Yamamoto, Y. J. Org. Chem. 1997, 62, 6274-6282. (16) Gralla, G.; Wibbeling, B.; Hoppe, D. Org. Lett. 2002, 4, 2193-2196.
Org. Lett., Vol. 4, No. 13, 2002
